Phenotypic characterization and cancer risk related to homozygous and heterozygous mutations in the ataxia-telangiectasia mutated gene

The ataxia-telangiectasia mutated (ATM) gene plays a critical role in DNA damage repair and functions as a tumor suppressor. Homozygous mutations in the ATM gene cause ataxia-telangiectasia (A-T), a rare autosomal recessive disorder characterized by progressive neurodegeneration, immunodeficiency, radiosensitivity, and a markedly increased risk of malignancy. In contrast, individuals carrying heterozygous ATM mutations are phenotypically normal but demonstrate an elevated susceptibility to cancer, particularly breast cancer. This review aimed to summarize current knowledge on the phenotypic manifestations associated with both homozygous and heterozygous ATM mutations and evaluate their relationship to cancer risk. A total of 98 published studies were reviewed, alongside data from established genetic databases including OMIM, GeneCards, UniProt, and GeneReviews. Evidence indicated that A-T patients with homozygous ATM mutations are at high risk for malignancies, with lymphoid cancers such as leukemia and lymphoma predominating in individuals under 20 years of age, while solid tumors are more frequently observed in adults. Heterozygous ATM mutation carriers exhibited a significantly increased risk of cancer, most notably breast cancer, with emerging data suggesting elevated risk in males as well. Further large-scale and longitudinal studies are required to more precisely quantify cancer risk associated with ATM mutations and to improve surveillance, genetic counselling, and clinical management strategies.